Alberto Baroja‐Mazo

Instituto Murciano de Investigación Biosanitaria

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Pablo Pelegrı́n

Instituto Murciano de Investigación Biosanitaria

J.A. Pons

Hospital Universitario Virgen de la Arrixaca

L. Martínez‐Alarcón

Hospital Universitario Virgen de la Arrixaca

Beatriz Revilla‐Nuin

Instituto Murciano de Investigación Biosanitaria

Carlos Martínez

Universidad de Murcia

Pablo Ramı́rez

Hospital Universitario Virgen de la Arrixaca

Pascual Parrilla

Hospital Universitario Virgen de la Arrixaca

Víctor López‐López

Instituto Murciano de Investigación Biosanitaria

Juan José Martínez-García

Universidad de Murcia

Laura Hurtado‐Navarro

Instituto Murciano de Investigación Biosanitaria

Cooperative Institutions

Hospital Universitario Virgen de la Arrixaca

Instituto Murciano de Investigación Biosanitaria

Universidad de Murcia

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Hospital General Universitario Gregorio Marañón

Universidad Complutense de Madrid

Universitat de Barcelona

Hospital Clínic de Barcelona

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Soluble P2X7 Receptor Is Elevated in the Plasma of COVID-19 Patients and Correlates With Disease Severity

Frontiers in Immunology (2022)

Julio García-Villalba Laura Hurtado‐Navarro Alejandro Peñín‐Franch Cristina Molina‐López L. Martínez‐Alarcón

Inflammation is a tightly coordinated response against bacterial and viral infections, triggered by the production of pro-inflammatory cytokines. SARS-CoV-2 infection induces COVID-19 disease, characterized by an inflammatory response mediated through the activation of the NLRP3 inflammasome, which results in the production of IL-1β and IL-18 along with pyroptotic cell death. The NLRP3 inflammasome could be also activated by sterile danger signals such as extracellular ATP triggering the purinergic P2X7 receptor. Severe inflammation in the lungs of SARS-CoV-2-infected individuals is associated with pneumonia, hypoxia and acute respiratory distress syndrome, these being the causes of death associated with COVID-19. Both the P2X7 receptor and NLRP3 have been considered as potential pharmacological targets for treating inflammation in COVID-19. However, there is no experimental evidence of the involvement of the P2X7 receptor during COVID-19 disease. In the present study, we determined the concentration of different cytokines and the P2X7 receptor in the plasma of COVID-19 patients and found that along with the increase in IL-6, IL-18 and the IL-1 receptor antagonist in the plasma of COVID-19 patients, there was also an increase in the purinergic P2X7 receptor. The increase in COVID-19 severity and C-reactive protein concentration positively correlated with increased concentration of the P2X7 receptor in the plasma, but not with the IL-18 cytokine. The P2X7 receptor was found in the supernatant of human peripheral blood mononuclear cells after inflammasome activation. Therefore, our data suggest that determining the levels of the P2X7 receptor in the plasma could be a novel biomarker of COVID-19 severity.

Coronavirus

10.3389/fimmu.2022.894470

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Citations (24)

Purinergic P2X7 receptor expression increases in leukocytes from intra-abdominal septic patients

Frontiers in Immunology (2023)

Helios Martínez‐Banaclocha Carlos García-Palenciano L. Martínez‐Alarcón J. Amores Fatima Martín‐Sánchez

Inflammation is a tightly coordinated response of the host immune system to bacterial and viral infections, triggered by the production of inflammatory cytokines. Sepsis is defined as a systemic inflammatory response followed by immunosuppression of the host and organ dysfunction. This imbalance of the immune response increases the risk of mortality of patients with sepsis, making it a major problem for critical care units worldwide. The P2X7 receptor plays a crucial role in activating the immune system by inducing the activation of peripheral blood mononuclear cells. In this study, we analyzed a cohort of abdominal origin septic patients and found that the expression of the P2X7 receptor in the plasma membrane is elevated in the different subsets of lymphocytes. We observed a direct relationship between the percentage of P2X7-expressing lymphocytes and the early inflammatory response in sepsis. Additionally, in patients whose lymphocytes presented a higher percentage of P2X7 surface expression, the total lymphocytes populations proportionally decreased. Furthermore, we found a correlation between elevated soluble P2X7 receptors in plasma and inflammasome-dependent cytokine IL-18. In summary, our work demonstrates that P2X7 expression is highly induced in lymphocytes during sepsis, and this correlates with IL-18, along with other inflammatory mediators such as IL-6, IL-8, and procalcitonin.

Procalcitonin

Immunosuppression

10.3389/fimmu.2023.1297249

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Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta‐analysis

Liver International (2023)

Christian Appenzeller‐Herzog Aurélie Rosat Tim Mathes Alberto Baroja‐Mazo Andrzej Chruscinski

Abstract Background & Aims Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term “pre‐withdrawal time”. To clarify the impact of pre‐withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta‐analysis. Methods We systematically interrogated the literature for LT recipient ISW studies reporting pre‐withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre‐withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time‐response curves were calculated using random‐effects meta‐analyses. Results We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study‐level risk of bias was heterogeneous. Mean pre‐withdrawal time was greater by 427 days [95% confidence interval (CI) 67–788] in OT compared to non‐OT patients. This increase was potentiated to 799 days (95% CI 369–1229) or 1074 days (95% CI 685–1463) when restricting analysis to adult or European study participants. In time‐response meta‐analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4–10%) per year after LT (GRADE low‐ and moderate‐certainty of evidence, respectively). Conclusions Our data support the impact of pre‐withdrawal time in ISW decision‐making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.

Immunosuppression

10.1111/liv.15764

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Early endosome autoantigen 1 regulates IL-1β release upon caspase-1 activation independently of gasdermin D membrane permeabilization

Scientific Reports (2019)

Alberto Baroja‐Mazo Vincent Compan Fatima Martín‐Sánchez Ana Tapia‐Abellán Isabelle Couillin

Abstract Unconventional protein secretion represents an important process of the inflammatory response. The release of the pro-inflammatory cytokine interleukin (IL)-1β which burst during pyroptosis as a consequence of gasdermin D plasma membrane pore formation, can also occur through other unconventional secretion pathways dependent on caspase-1 activation. However, how caspase-1 mediates cytokine release independently of gasdermin D remains poorly understood. Here we show that following caspase-1 activation by different inflammasomes, caspase-1 cleaves early endosome autoantigen 1 (EEA1) protein at Asp 127/132 . Caspase-1 activation also results in the release of the endosomal EEA1 protein in a gasdermin D-independent manner. EEA1 knock-down results in adecreased release of caspase-1 and IL-1β, but the pyroptotic release of other inflammasome components and lactate dehydrogenase was not affected. This study shows how caspase-1 control the release of EEA1 and IL-1β in a pyroptotic-independent manner.

Pyroptosis

10.1038/s41598-019-42298-4

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Proteomics in Liver Transplantation: A Systematic Review

Frontiers in Immunology (2021)

Víctor López‐López Fernando Pérez‐Sanz Carlos de Torre‐Minguela Josefa Marco-Abenza R Robles

Background Although proteomics has been employed in the study of several models of liver injury, proteomic methods have only recently been applied not only to biomarker discovery and validation but also to improve understanding of the molecular mechanisms involved in transplantation. Methods The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and the guidelines for performing systematic literature reviews in bioinformatics (BiSLR). The PubMed, ScienceDirect, and Scopus databases were searched for publications through April 2020. Proteomics studies designed to understand liver transplant outcomes, including ischemia-reperfusion injury (IRI), rejection, or operational tolerance in human or rat samples that applied methodologies for differential expression analysis were considered. Results The analysis included 22 studies after application of the inclusion and exclusion criteria. Among the 497 proteins annotated, 68 were shared between species and 10 were shared between sample sources. Among the types of studies analyzed, IRI and rejection shared a higher number of proteins. The most enriched pathway for liver biopsy samples, IRI, and rejection was metabolism, compared to cytokine-cytokine receptor interactions for tolerance. Conclusions Proteomics is a promising technique to detect large numbers of proteins. However, our study shows that several technical issues such as the identification of proteoforms or the dynamic range of protein concentration in clinical samples hinder the successful identification of biomarkers in liver transplantation. In addition, there is a need to minimize the experimental variability between studies, increase the sample size and remove high-abundance plasma proteins.

Biomarker Discovery

Identification

10.3389/fimmu.2021.672829

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Citations (5)

The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

Nature Immunology (2014)

Alberto Baroja‐Mazo Fatima Martín‐Sánchez Ana Isabel Gómez Córdoba Carlos Martínez J. Amores

AIM2

NALP3

10.1038/ni.2919

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Citations (715)

Dynamics of Ischemia/Reperfusion Injury Markers During Normothermic Liver Machine Perfusion

Transplantation Direct (2024)

A. Marcos Luis Rodríguez-Bachiller Alberto Baroja‐Mazo Álvaro Morales Paloma Fernández-Cáceres

Background. A comprehensive mechanistic assessment of normothermic machine perfusion (NMP) is an essential step toward identifying biomarkers to assess liver viability. Although some studies have evaluated the effect of NMP on inflammation markers, there are other key pathological mechanisms involved in ischemia/reperfusion injury (IRI) that have not yet been evaluated. Methods. Eight human donor livers preserved by NMP were included to analyze IRI during preservation. Concentrations of several biomarkers involved in different biological processes of IRI were measured in the perfusate. Results. Perfusate levels of intercellular adhesion molecule 1, P-selectin, vascular cell adhesion molecule 1, metalloproteinase with thrombospondin motif type 1, member 13, phospholipase A2 group VII, and syndecan-1 progressively increased during NMP. Noteworthy, perfusate lactate levels showed a strong correlation with C-X-C motif chemokine ligand 10 ( P = 0.001), intercellular adhesion molecule 1 ( P = 0.01), and urokinase plasminogen activator ( P = 0.001). Conclusions. Perfusate lactate correlates with the main underlying biological mechanisms occurring in the NMP environment. Moreover, several IRI biomarkers accumulate during NMP, which may limit the extent of the benefits of this technology.

Machine Perfusion

10.1097/txd.0000000000001728

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P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production

Frontiers in Immunology (2017)

María Barberà-Cremades Ana Isabel Gómez Córdoba Alberto Baroja‐Mazo L. Martínez‐Alarcón Carlos Martínez

Tumor necrosis factor (TNF)-α is a major pro-inflammatory cytokine produced in response to toll-like receptor stimulation. TNF-α release is controlled by the activity of TNF-α converting enzyme (TACE) that cut membrane-bound TNF-α to shed its ectodomain as a soluble cytokine. The purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is activated in response to elevated concentrations of extracellular ATP and induces different pro-inflammatory pathways in macrophages to establish an inflammatory response. P2X7 receptor promotes the activation of the inflammasome and the release of interleukin-1β, the production of inflammatory lipids, and the generation of reactive oxygen species. In this study, we analyzed the mechanism of P2X7 receptor responsible of TNF-α release after priming macrophages with LPS doses ≤100 ng/ml. We found that P2X7 receptor increases the extracellular activity of TACE through the release of the mature form of TACE in exosomes. This effect was blocked using P2X7 receptor inhibitors or in macrophages obtained from P2X7 receptor-deficient mice. Elevation of intracellular Ca2+ and p38 mitogen-activated protein kinase after P2X7 receptor activation were involved in the release of TACE, which was able to process TNF-α on nearby expressing cells. Finally, we observed an increase of TNF-α in the peritoneal lavage of mice treated with LPS and ATP. In conclusion, P2X7 receptor induces the release of TACE in exosomes to the extracellular compartment that could amplify the pro-inflammatory signal associated to this receptor. These results are important for the development of therapeutics targeting P2X7 receptor.

10.3389/fimmu.2017.00862

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Citations (58)

Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation

International Journal of Molecular Sciences (2022)

Fernando Lucas‐Ruiz Alejandro Peñín‐Franch J.A. Pons Pablo Ramírez Pablo Pelegrı́n

The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1β and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia–reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.

Pyroptosis

10.3390/ijms232214396

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Citations (19)

Selecting the Appropriate Downstaging and Bridging Therapies for Hepatocellular Carcinoma: What Is the Role of Transarterial Radioembolization? A Pooled Analysis

Cancers (2023)

Víctor López‐López Kohei Miura Christoph Kuemmerli Antonio Capel Dilmurodjon Eshmuminov

Background: Transarterial radioembolization in HCC for LT as downstaging/bridging has been increasing in recent years but some indication criteria are still unclear. Methods: We conducted a systematic literature search of primary research publications conducted in PubMed, Scopus and ScienceDirect databases until November 2022. Relevant data about patient selection, HCC features and oncological outcomes after TARE for downstaging or bridging in LT were analyzed. Results: A total of 14 studies were included (7 downstaging, 3 bridging and 4 mixed downstaging and bridging). The proportion of whole liver TARE was between 0 and 1.6%. Multiple TARE interventions were necessary for 16.7% up to 28% of the patients. A total of 55 of 204 patients across all included studies undergoing TARE for downstaging were finally transplanted. The only RCT included presents a higher tumor response with the downstaging rate for LT of TARE than TACE (9/32 vs. 4/34, respectively). Grade 3 or 4 adverse effects rate were detected between 15 and 30% of patients. Conclusions: TARE is a safe therapeutic option with potential advantages in its capacity to necrotize and reduce the size of the HCC for downstaging or bridging in LT.

Complete response

10.3390/cancers15072122

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Citations (10)